HIV pathogenesis can be summarized as a state of immunodeficiency, reflected by a decline in CD4+ T cell numbers, occurring in a setting of immunosuppression, reflected by levels of HIV in the blood. The peripheral blood CD4+ T cell count reflects the current level of immune competence while the plasma level of HIV RNA reflects the rate at which the CD4 T cell count can be expected to decline. In general, patients do not become ill until the CD4 count drops below a critical threshold. The level of this threshold is dependent upon the amounts of virus in the blood. The higher the plasma levels of HIV, the faster the CD4+ T cell count will decline and the higher the CD4+ T cell count at which opportunistic illnesses will develop. Current combination antiretroviral treatment regimens are able to reduce levels of virus and allow for a degree of recovery of the immune system. Unfortunately, these drugs are also associated with a significant degree of side effects that become more pronounced over time. The purpose of this project is to develop novel approaches to therapy that target the immune system rather than the virus. A major focus of this project is to examine the role of the T cell derived growth and survival factor interleukin-2 (IL-2) as a treatment strategy based upon expanding the size of the CD4 T cell pool. Additional work examines the role of immunosuppressive therapy, the role of the cytokine IL-7 and the role of genetic modification of CD4+ T cells to make them more resistant to HIV infection. Over the past year, utilizing in vivo labeling techniques it has been shown that the increases in CD4+ T cell counts seen with intermittent IL-2 are due to profound increases in the survival of naive and central memory CD4+ T cells. In other IL-2 related studies, follow-up continues on a cohort of approximately 6000 patients enrolled in two phase III clinical endpoint studies (ESPRIT and SILCAAT). In other work, ten subjects received infusions of genetically modified CD4+ T cells from their identical twin siblings. These cells were modified to express anti-sense nucleic acids and a protein designed to interfere with the function of the rev gene. Through molecular analyses, the CD4+ T cells expressing the foreign genes were found to have a survival advantage over the control cells.